Neural tube defects (NTDs) are among the most common congenital anomalies reported in the United States, and periconceptional folic acid supplementation has been found to decrease the recurrence risk of NTDs. The primary aim of this US Preventive Services Task Force study was to review the existing data on use of folic acid supplementation for preventing NTDs and to provide an updated/revised recommendation statement. Since 1998, grain products in the United States have been fortified with folate in order to provide for the micronutritional needs of the population and to decrease the incidence of NTDs. Studies (in English language) addressing folic acid supplementation in women were extracted from databases such as MEDLINE, Cochrane Library, EMBASE, and trial registries through January 28, 2016, with ongoing surveillance through November 11, 2016, and were independently reviewed by 2 investigators. References and experts on the effects of folic acid intake were also consulted. The primary outcomes and measures of the review were NTDs and harms of treatment (twinning and respiratory outcomes).
In total, 24 studies (N > 58,860) were included in the review (exclusion criteria being poor-quality studies; studies of prepubertal girls, men, women without the potential for childbearing, NTD recurrence; and studies that were conducted in developing countries). A landmark Hungarian study demonstrated the effectiveness of folic acid in prevention of NTDs, with the incidence of NTDs with folic acid supplementation reported as 0% versus 0.25% in control subjects (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.03-0.65; n = 4862). Between 1984 and 1996, the demonstrated beneficial associations between folic acid and NTD prevention were reported as 0.11 to 0.27 (n = 19,982). Three of 4 case-control studies with data from 1976 through 1998 reportedORs ranging from 0.6 to 0.7 (n > 7121). Combined data from these studies led to fortification of grains with folate in the United States in 1998.
Studies since 1998 have relied on observational data using case-control designs, and in these more recent studies, the protective association of additional folate supplementation beyond food fortification has not been demonstrated, with ORs ranging from 0.93 to 1.4 and CI spanning the null (n > 13,990). Folate supplementation, however, has not been associated with evidence of adverse effects, such as an increased risk of twinning or childhood respiratory illnesses, or with variation in these outcomes by timing or dose. In 1 trial (OR, 1.40 [95% CI, 0.89-2.21]; n = 4767) and 1 cohort study (OR, 1.04 [95% CI, 0.91-1.18]; n = 2620), there was no significantly increased risk of twinning. Three systematic reviews found no consistent evidence of increased risk of asthma (OR, 1.06 [95% CI, 0.99-1.14]; n = 14 438), wheezing, or allergy. Hence, this review of relevant studies posits that newer post-fortification studies have not supported a protective association of additional folic acid supplementation, although such studies have the potential for misclassification and recall bias.